{PDOC51962} {PS51962; COV_NSP1} {PS51963; BCOV_NSP1_C} {BEGIN} ************************************************************************************************** * Coronavirus (CoV) Nsp1 globular and Betacoronavirus (BetaCoV) Nsp1 C-terminal domains profiles * ************************************************************************************************** Coronaviruses (CoVs) are enveloped positive-strand RNA viruses that infect many species, including humans, other mammals, and birds. After infection, the host may develop respiratory, bowel, liver, and neurological diseases. Coronaviruses are divided into four genera: Alphacoronavirus, Betacoronavirus, Gammacoronavirus, and Deltacoronavirus. The ideal hosts of AlphaCoV and BetaCoV are mammals, and GammaCoV primarily infects birds, while DeltaCoV has been identified in both mammals and birds. SARS, SARS-CoV-2, BatCoV RaTG13 and Bat-SARS-like coronavirus (BATSL-CoVZXC21 and BAT-SL-CoVZC45) belong to the Sarbecovirus subgenus of BetaCoV [E1]. The CoV replicase gene encodes two overlapping polyproteins, termed pp1a and pp1ab, which mediate viral replication and transcription. The polypeptides pp1a and pp1ab are processed by the action of a main protease (Nsp5) (see ) and of one or two papain-like proteases (PLpro) (see ) found in Nsp3 into non-structural proteins (Nsps) that predominantly play a role in replication and transcription. Although the CoV genome is highly conserved within genera, Nsp1, which is located at the N terminus of the replicase polyprotein pp1a, is responsible for the majority of variation. Nsp1 is a critical virulence factor of coronaviruses and plays key roles in suppressing host gene expression, which facilitates viral replication and immune evasion. Nsp1 is a characteristic feature of AlphaCoVs and BetaCoVs, which exhibits both functional conservation and mechanistic diversity in inhibiting host gene expression and antiviral responses. Only AlphaCoVs and BetaCoVs encode Nsp1, whereas DeltaCoVs and GammaCoVs lack this protein. The sizes of AlphaCoV Nsp1 and BetaCoV Nsp1 differ; the AlphaCoVs encode Nsp1 proteins of ~9 kDa, which are substantially smaller than the ~20-kDa Nsp1 proteins of BetaCoVs. Although the sequence homologies among CoV Nsp1 proteins are low, the core structures share a relatively conserved domain. This high structural similarity may explain why CoV Nsp1 has the conserved biological function of inhibiting host gene expression. However, the critical region of BetaCoV Nsp1 required to inhibit protein synthesis is different from that of AlphaCoV Nsp1 [1,2,3,4]. In addition to the globular domain, BetaCoV Nsp1s contain a C-terminal domain. The Sarbecovirus Nsp1 C-terminal domain binds to the mRNA channel of the 40S ribosome, where it interferes with mRNA binding and inhibits host protein translation. The 5’ UTR of Sarbecovirus mRNA removes this inhibition by binding to the Nsp1 globular domain. This inhibition mechanism may be unique to Sarbecoviruses, because the C-terminal region of Nsp1 is shorter in AlphaCoVs and is not highly conserved amongst other BetaCoVs, including MERS-CoV [5,6,7,8]. The CoV Nsp1 globular domain displays a six-stranded beta-barrel fold with a long alpha helix on the rim of the barrel (see ). The core of the beta-barrel is highly hydrophobic [1,2,4]. The BetaCoV Nsp1 C-terminal domain comprises two alpha helices and two short loops (see ) [5,6,7]. The profiles we developed cover respectively the entire CoV Nsp1 globular and BetaCoV Nsp1 C-terminal domains. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Sequences known to belong to this class detected by the profile: ALL. -Other sequence(s) detected in Swiss-Prot: NONE. -Last update: December 2021 / Profile revised. [ 1] Jansson A.M. "Structure of alphacoronavirus transmissible gastroenteritis virus nsp1 has implications for coronavirus nsp1 function and evolution." J. Virol. 87:2949-2955(2013). PubMed=23269811; DOI=10.1128/JVI.03163-12 [ 2] Shen Z., Ye G., Deng F., Wang G., Cui M., Fang L., Xiao S., Fu Z.F., Peng G. "Structural Basis for the Inhibition of Host Gene Expression by Porcine Epidemic Diarrhea Virus nsp1." J. Virol. 92:0-0(2018). PubMed=29237834; DOI=10.1128/JVI.01896-17 [ 3] Shen Z., Wang G., Yang Y., Shi J., Fang L., Li F., Xiao S., Fu Z.F., Peng G. "A conserved region of nonstructural protein 1 from alphacoronaviruses inhibits host gene expression and is critical for viral virulence." J. Biol. Chem. 294:13606-13618(2019). PubMed=31350335; DOI=10.1074/jbc.RA119.009713 [ 4] Semper C., Watanabe N., Savchenko A. "Structural characterization of nonstructural protein 1 from SARS-CoV-2." iScience 24:101903-101903(2021). PubMed=33319167; DOI=10.1016/j.isci.2020.101903 [ 5] Thoms M., Buschauer R., Ameismeier M., Koepke L., Denk T., Hirschenberger M., Kratzat H., Hayn M., Mackens-Kiani T., Cheng J., Straub J.H., Stuerzel C.M., Froehlich T., Berninghausen O., Becker T., Kirchhoff F., Sparrer K.M.J., Beckmann R. "Structural basis for translational shutdown and immune evasion by the Nsp1 protein of SARS-CoV-2." Science 369:1249-1255(2020). PubMed=32680882; DOI=10.1126/science.abc8665 [ 6] Schubert K., Karousis E.D., Jomaa A., Scaiola A., Echeverria B., Gurzeler L.-A., Leibundgut M., Thiel V., Muehlemann O., Ban N. "SARS-CoV-2 Nsp1 binds the ribosomal mRNA channel to inhibit translation." Nat. Struct. Mol. Biol. 27:959-966(2020). PubMed=32908316; DOI=10.1038/s41594-020-0511-8 [ 7] Yuan S., Peng L., Park J.J., Hu Y., Devarkar S.C., Dong M.B., Shen Q., Wu S., Chen S., Lomakin I.B., Xiong Y. "Nonstructural Protein 1 of SARS-CoV-2 Is a Potent Pathogenicity Factor Redirecting Host Protein Synthesis Machinery toward Viral RNA." Mol. Cell. 80:1055-1066.e6(2020). PubMed=33188728; DOI=10.1016/j.molcel.2020.10.034 [ 8] Shi M., Wang L., Fontana P., Vora S., Zhang Y., Fu T.-M., Lieberman J., Wu H. "SARS-CoV-2 Nsp1 suppresses host but not viral translation through a bipartite mechanism." bioRxiv 0:0-0(2020). PubMed=32995777; DOI=10.1101/2020.09.18.302901 [E1] https://viralzone.expasy.org/30?outline=all_by_species -------------------------------------------------------------------------------- PROSITE is copyrighted by the SIB Swiss Institute of Bioinformatics and distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives (CC BY-NC-ND 4.0) License, see https://prosite.expasy.org/prosite_license.html -------------------------------------------------------------------------------- {END}